Treatment with modified heparins inhibits experimental metastasis formation and leads, in some animals, to long-term survival.

Two chemically modified heparins with low anticoagulant activity were studied in terms of their antimetastatic activity in the B16-BL6 melanoma model. The two heparins were a very low molecular weight heparin (VLMW-H) and a low molecular weight heparin with 100% succinylation of desulfated N groups (Succ100-LMW-H). Both heparins, VLMW-H more so than Succ100-LMW-H, were highly effective in decreasing the number of lung metastasis on day 21 when administered once subcutaneously 10 min before intravenous injection of melanoma cells or 2 times/week for 3 weeks. When the time of survival was measured, both heparins did not significantly prolong survival when administered once before injection of the tumor cells. When a repeated treatment schedule was adopted over 3 weeks, both heparins led to a slight, yet significant prolongation of survival. When the repeated treatment protocol was continued beyond 3 weeks, a highly significant prolongation of survival was observed with VLMW-H and there were some long-term survivors (20% for VLMW-H and 10% for Succ-LMW-H) that remained disease-free after discontinuation of therapy on day 90. The present results confirm and reinforce the concept that heparins with reduced anticoagulant activity may have interesting therapeutic applications in the prevention of tumor metastasis.

In vitro and in vivo properties of an anti-CD5-momordin immunotoxin on normal and neoplastic T lymphocytes.

An anti-CD5 monoclonal antibody (mAb) was linked to the plant toxin momordin, a type-1 ribosome-inactivating protein purified from Momordica charantia. The in vitro cytotoxicity of the immunotoxin was evaluated as the inhibition of protein and/or DNA synthesis on isolated peripheral blood mononuclear cells (PBMC) and on human T cell leukemia Jurkat. The potency of the immunotoxin on PBMC was very high (IC50 = 1 - 10 pM) and was not affected by blood components. The conjugate was also very efficient in the inhibition of the proliferative response in a mixed lymphocyte reaction (IC50 = 10 pM). Moreover, the in vitro performance of the immunotoxin compared favorably with those reported for other anti-CD5-based immunoconjugates containing ricin A chain. The in vivo activity of the immunotoxin was assessed in the model of nu/nu mice bearing Jurkat leukemia. A significant inhibition of the tumour development (80%, P < 0.01) in the animals treated with immunotoxin was observed. Taken together, the in vitro and in vivo results suggest that the anti-CD5-momordin conjugate may be useful for graft-versus-host disease therapy and potentially in the treatment of CD5-positive leukemias and lymphomas.